Bendell Johanna C, Patel Manish R, Infante Jeffrey R, Kurkjian Carla D, Jones Suzanne F, Pant Shubham, Burris Howard A, Moreno Ofir, Esquibel Vanessa, Levin Wendy, Moore Kathleen N
Sarah Cannon Research Institute, Nashville, Tennessee; Tennessee Oncology PLLC, Nashville, Tennessee.
Cancer. 2015 Apr 1;121(7):1056-63. doi: 10.1002/cncr.29155. Epub 2014 Nov 19.
The current phase 1, open-label, dose escalation study was conducted to establish the safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity of the novel mitochondrial inhibitor ME-344 in patients with refractory solid tumors.
Patients with refractory solid tumors were treated in a 3 + 3 dose escalation design. ME-344 was administered via intravenous infusion on days 1, 8, and 15 of the first 28-day cycle and weekly thereafter. Pharmacokinetics was assessed on days 1 and 15 of the first cycle.
A total of 30 patients (median age, 65 years; 67% of whom were female) received ME-344. There were 5 dose-limiting toxicities reported. Four patients developed grade 3 neuropathy (2 patients each at doses of 15 mg/kg and 20 mg/kg) and 1 patient treated at a dose of 10 mg/kg developed a grade 3 acute myocardial infarction (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]). The maximum tolerated dose (MTD) was defined as 10 mg/kg weekly. The most common adverse events were nausea, dizziness, and fatigue. At the MTD of 10 mg/kg, the maximal plasma concentration (Cmax) was 25.8 µg/mL and the area under the concentration curve from time zero to infinity was 25.9 hour*µg/mL. One patient with small cell lung cancer achieved a partial response for ≥ 52 weeks. Four patients had prolonged stable disease (1 patient each with urothelial carcinoma [47 weeks], carcinoid tumor [≥ 40 weeks], cervical leiomyosarcoma [39 weeks], and cervical cancer [≥ 31 weeks]).
The once-weekly administration of ME-344 was generally well tolerated in the current study, a first-in-human study; dose-limiting neuropathy was noted, but not at the MTD. Exposures at the 10-mg/kg dose level suggest a sufficient therapeutic index. The preliminary clinical activity as a monotherapy supports the further clinical development of ME-344 in combination with chemotherapy.
当前进行的1期开放标签剂量递增研究旨在确定新型线粒体抑制剂ME-344在难治性实体瘤患者中的安全性、耐受性、药代动力学特征及初步抗肿瘤活性。
难治性实体瘤患者采用3+3剂量递增设计进行治疗。ME-344在前28天周期的第1、8和15天通过静脉输注给药，此后每周给药一次。在第一个周期的第1天和第15天评估药代动力学。
共有30例患者（中位年龄65岁；67%为女性）接受了ME-344治疗。报告了5例剂量限制性毒性。4例患者发生3级神经病变（2例剂量为15mg/kg，2例剂量为20mg/kg），1例剂量为10mg/kg的患者发生3级急性心肌梗死（毒性根据美国国立癌症研究所不良事件通用术语标准[第4.03版]分级）。最大耐受剂量（MTD）定义为每周10mg/kg。最常见的不良事件为恶心、头晕和疲劳。在10mg/kg的MTD剂量下，最大血浆浓度（Cmax）为25.8μg/mL，从零至无穷大的浓度曲线下面积为25.9小时*μg/mL。1例小细胞肺癌患者获得了≥52周的部分缓解。4例患者病情长期稳定（1例分别为尿路上皮癌[47周]、类癌肿瘤[≥40周]、宫颈平滑肌肉瘤[39周]和宫颈癌[≥31周]）。
在当前这项首次人体研究中，ME-344每周一次给药总体耐受性良好；注意到有剂量限制性神经病变，但在MTD剂量下未出现。10mg/kg剂量水平的暴露表明有足够的治疗指数。作为单一疗法的初步临床活性支持ME-344与化疗联合的进一步临床开发。
